The inheritance of APOE?4 allele is the strongest genetic risk factor for late onset Alzheimer?s disease (LOAD). In fact, the inheritance of APOE?4 allele is the strongest known genetic risk factor in human pathology, but the mechanism is poorly understood. In contrast, APOE?2 allele is protective for AD and age-related diseases AD. While APOE has been associated with critical cellular functions such as oxidative processes, in?ammation, glial cell and neuronal homeostasis, none of those can be dissociated from binding, transport and delivery of choles- terol and phospholipids to di?erent cell types by APOE containing lipoprotein particles. It is also uniformly ac- cepted that the above functions are APOE-isoform speci?c. Our preliminary data demonstrates that phospholipid composition of APOE?3/3 and APOE?4/4 AD brain differs significantly. Most prominent were changes in lipid classes that are critical in regulation of normal mitochondrial function and dynamics, but also in execution of metabolic cascades part of regulated intracellular protein degradation known as autophagy and mitophagy. We also found significant APOE isoform-specific differences between the transcriptomic profiles of the AD samples that substantiate molecular explanation of specific AD pathological changes in brain, based on perturbed gene expression. Our preliminary data also demonstrates that there is a significant difference in the phospholipid content of native APOE2, APOE3- and APOE4- lipoproteins suggesting that that they may affect differentially surface immune receptors and initiate different signal transduction cascades. We hypothesize that the APOE isoform-speci?c e?ects on phenotype are driven by the di?erent phospholipid composition of APOE lipid particles and/or by the di?erential e?ect of APOE isoforms on brain transcriptome and lipidome. In the First SA, we will establish the association of APOE alleles with AD brain transcriptome and lipidome and determine the allele specific impact on mitochondrial function and dynamics. We will use postmor- tem brain samples from AD patients and controls of different APOE genotypes to determine differences in tran- scriptomes and lipidomes within and between genotypes. We will generate and analyze correlated/co-expressed gene networks based on APOE allele associated differentially expressed genes and perform correlation analyses to identify associations between genes and lipids in brain. In the Second SA, we will investigate APOE isoform- dependent epigenetic and transcriptomic changes in AD brain and APOE Targeted Replacement mice. We will determine the enrichment of histone marks in specific cell types isolated from human AD and control brains and will examine APOE allele specific correlations to gene expression profiles. Next, we will examine the effect of aging on epigenome and transcriptome in distinct brain cell types of human APOE TR mice. In the Third SA, we will determine how APOE2 lipoproteins counteract the acute deleterious effects of A?. The goals are to examine the effect of APOE2, E3 and E4 lipoproteins on: transcriptome of distinct brain cell populations and cognition in mice following intracranial injection of A??